title: Loss of PTEN is associated with aggressive behavior in ERG-positive prostate cancer.
abstract: BACKGROUND
  The associations of ERG overexpression with clinical behavior and molecular pathways of prostate cancer are incompletely known. We assessed the association of ERG expression with AR, PTEN, SPINK1, Ki-67, and EZH2 expression levels, deletion, and mutations of chromosomal region 3p14 and TP53, and clinicopathologic variables.
  
  
  METHODS
  The material consisted of 326 prostatectomies, 166 needle biopsies from men treated primarily with endocrine therapy, 177 transurethral resections of castration-resistant prostate cancers (CRPC), and 114 CRPC metastases obtained from 32 men. Immunohistochemistry, FISH, and sequencing was used for the measurements.
  
  
  RESULTS
  ERG expression was found in about 45% of all patient cohorts. In a multivariate analysis, ERG expression showed independent value of favorable prognosis (P = 0.019). ERG positivity was significantly associated with loss of PTEN expression in prostatectomy (P = 0.0348), and locally recurrent CRPCs (P = 0.0042). Loss of PTEN expression was associated (P = 0.0085) with shorter progression-free survival in ERG-positive, but not in negative cases. When metastases in each subject were compared, consistent ERG, PTEN, and AR expression as well as TP53 mutations were found in a majority of subjects.
  
  
  CONCLUSIONS
  A similar frequency of ERG positivity from early to late stage of the disease suggests lack of selection of ERG expression during disease progression. The prognostic significance of PTEN loss solely in ERG-positive cases indicates interaction of these pathways. The finding of consistent genetic alterations in different metastases suggests that the major genetic alterations take place in the primary tumor.
  
  
  CONCLUSIONS
  Interaction of PTEN and ERG pathways warrants further studies.
authors.affiliation: Authors' Affiliations: Institute of Biomedical Technology and Institute of Signal Processing, Prostate Cancer Research Center, BioMediTech, Department of Urology, School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland; Departments of Pathology and Urology, Jikei University School of Medicine, Minato-ku, Tokyo; Department of Urology, Toho University Sakura Medical Center, Sakura, Chiba, Japan; Departments of Pathology and Urology, Johns Hopkins University, Baltimore, Maryland; and Department of Clinical Chemistry, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Katri A
authors.initials: KA
authors.lastname: Leinonen
authors.forename: Outi R
authors.initials: OR
authors.lastname: Saramäki
authors.forename: Bungo
authors.initials: B
authors.lastname: Furusato
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kimura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Shin
authors.initials: S
authors.lastname: Egawa
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Kerri
authors.initials: K
authors.lastname: Keiger
authors.forename: Sung
authors.initials: S
authors.lastname: Ho Hahm
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.forename: Teemu T
authors.initials: TT
authors.lastname: Tolonen
authors.forename: Ulf-Håkan
authors.initials: UH
authors.lastname: Stenman
authors.forename: Teuvo L J
authors.initials: TL
authors.lastname: Tammela
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.forename: G Steven
authors.initials: GS
authors.lastname: Bova
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D015331:Cohort Studies; D018572:Disease-Free Survival; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009362:Neoplasm Metastasis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016612:Paraffin Embedding; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D064129:Prostatic Neoplasms, Castration-Resistant / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000071230:Transcriptional Regulator ERG; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; C495901:TP53 protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human